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dc.contributor.authorButton, RW
dc.contributor.authorRoberts, SL
dc.contributor.authorWillis, TL
dc.contributor.authorHanemann, CO
dc.contributor.authorLuo, S
dc.date.accessioned2018-03-20T09:16:54Z
dc.date.available2018-03-20T09:16:54Z
dc.date.issued2017-07-03
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/10026.1/11110
dc.description.abstract

Autophagy comprises the processes of autophagosome synthesis and lysosomal degradation. In certain stress conditions, increased autophagosome synthesis may be associated with decreased lysosomal activity, which may result in reduced processing of the excessive autophagosomes by the rate-limiting lysosomal activity. Thus, the excessive autophagosomes in such situations may be largely unfused to lysosomes, and their formation/accumulation under these conditions is assumed to be futile for autophagy. The role of cytotoxicity in accumulating autophagosomes (representing synthesis of autophagosomes subsequently unfused to lysosomes) has not been investigated previously. Here, we found that accumulation of autophagosomes compromised cell viability, and this effect was alleviated by depletion of autophagosome machinery proteins. We tested whether reduction in autophagosome synthesis could affect cell viability in cell models expressing mutant huntingtin and α-synuclein, given that both of these proteins cause increased autophagosome biogenesis and compromised lysosomal activity. Importantly, partial depletion of autophagosome machinery proteins Atg16L1 and Beclin 1 significantly ameliorated cell death in these conditions. Our data suggest that production/accumulation of autophagosomes subsequently unfused to lysosomes (or accumulation of autophagosomes) directly induces cellular toxicity, and this process may be implicated in the pathogenesis of neurodegenerative diseases. Therefore, lowering the accumulation of autophagosomes may represent a therapeutic strategy for tackling such diseases.

dc.format.extent13599-13614
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherElsevier BV
dc.subjectautophagy
dc.subjectcell death
dc.subjectlysosome
dc.subjectmTOR complex (mTORC)
dc.subjectneurodegenerative disease
dc.subjectAnimals
dc.subjectAutophagosomes
dc.subjectCell Line, Tumor
dc.subjectCell Survival
dc.subjectCells, Cultured
dc.subjectEmbryo, Mammalian
dc.subjectGreen Fluorescent Proteins
dc.subjectHEK293 Cells
dc.subjectHumans
dc.subjectLysosomal-Associated Membrane Protein 2
dc.subjectLysosomal Membrane Proteins
dc.subjectLysosomes
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectMicroscopy, Electron, Transmission
dc.subjectNerve Tissue Proteins
dc.subjectNeurons
dc.subjectQa-SNARE Proteins
dc.subjectRNA Interference
dc.subjectRecombinant Fusion Proteins
dc.subjectTOR Serine-Threonine Kinases
dc.subjectTumor Cells, Cultured
dc.subjectVesicular Transport Proteins
dc.titleAccumulation of autophagosomes confers cytotoxicity
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/28673965
plymouth.issue33
plymouth.volume292
plymouth.publication-statusPublished online
plymouth.journalJournal of Biological Chemistry
dc.identifier.doi10.1074/jbc.M117.782276
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeUnited States
dcterms.dateAccepted2017-07-03
dc.identifier.eissn1083-351X
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1074/jbc.M117.782276
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-07-03
rioxxterms.typeJournal Article/Review
plymouth.funderTackling autophagy and apoptosis for the potential therapy of Huntington's Disease::MRC


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